Imidazopyridines as serotonergic 5-HT3 antagonists

ABSTRACT

The imidazopyridines compounds of the present invention are serotonergic 5-HT 3  antagonists. As such they are useful for the treatment of humans and animals wherein antagonism of 5-HT 3  receptors is beneficial. Therapy is indicated for, but not limited to, the treatment of anxiety, psychoses, depression (especially depression accompanied by anxiety), cognitive disorders, substance abuse dependence and withdrawal, gastrointestinal motility disturbancies (including esophageal reflux, dyspepsia, gastric stasis, irritable bowel syndrome), emesis caused by chemotherapeutic agents, and visceral pain. Additionally, the compounds of the present invention may find utility as enhancers of nasal absorption of bioactive compounds.

This is a continuation, of International appplication Ser. No. 92/01524,filed Mar. 4, 1992 which was a continuation-in-part of application Ser.No. 07/666,113, filed Mar. 7, 1991, now U.S. Pat. No. 5,260,303.

BACKGROUND OF THE INVENTION

The invention herein is directed to compounds and a method of treatinggastrointestinal motility disorders of a mammal by administering to themammal in need thereof a therapeutically effective amount of a compounddisclosed herein or a pharmaceutically acceptable salt thereof. Themethod can be practiced to treat gastrointestinal motility disorderssuch as gastroesophageal reflux, diseases characterized by delayedgastric emptying, ileus, irritable bowel syndrome, and the like. Thecompounds of the invention are serotonergic 5-HT₃ antagonists and assuch are useful for the treatment of conditions, for example, such asanxiety, psychoses and depression.

There are classes of compounds known for the treatment of suchdisorders. For example, azatetracycle compounds are disclosed inco-pending U.S. patent application Ser. No. 07/515,391 filed Apr. 27,1990, and N-Azabicyclo [3.3.0] octane amides of aromatic acids aredisclosed in co-pending application Ser. No. 07/406,205 filed Sep. 11,1989.

Aza-adamantyl compounds are disclosed in U.S. Pat. No. 4,816,453 and arementioned generically in U.K. Patent 2,152,049A and European application0189002A2.

Azabicyclic nonanes are disclosed in European Patent application0094742A2. Additional azabicyclic compounds are disclosed in U.S. Pat.Nos. 4,797,387 and 4,797,406.

Benzamides have been known as 5-HT₃ antagonists and as compoundspossessing gastrointestinal motility-enhancing properties. Benzamides ofthe following formula: ##STR1## compounds wherein X can be anazabicycloalkane moiety and which exhibit gastrointestinal motilityenhancing and/or 5-HT₃ antagonist properties are disclosed in EP0094742A2 and in U.S. Pat. No. 4,797,406. In addition, UK Patent2,152,049 discloses that certain benzamide derivatives exhibit serotoninM antagonistic activity.

Indoleamides of the following formula have also been described aspossessing gastrointestinal motility-enhancing and/or 5-HT₃ antagonistproperties: ##STR2## Compounds wherein X contains an aminergic sidechain or an azabicycloalkane moiety are described in U.S. Pat. No.4,797,406.

European patent publication number 0,230,718 discloses certainsubstituted benzamide derivatives, substituted with piperidinylanalogues as having gastrointestinal motility-enhancing and/orantiemetic activity and/or 5-HT₃ receptor antagonist activity.

SUMMARY OF THE INVENTION

The compounds of the present invention are serotonergic 5-HT₃antagonists. As such they are useful for the treatment of humans andanimals wherein antagonism of 5-HT₃ receptors is beneficial. Therapy isindicated for, but not limited to, the treatment of anxiety, psychoses,depression (especially depression accompanied by anxiety), cognitivedisorders, substance abuse dependence and withdrawal, gastrointestinalmotility disturbancies (including esophageal reflux, dyspepsia, gastricstasis, irritable bowel syndrome), emesis caused by chemotherapeuticagents, and visceral pain. Additionally, the compounds of the presentinvention may find utility as enhancers of nasal absorption of bioactivecompounds.

The invention herein is directed to compounds of the formula ##STR3##the stereoisomers and pharmaceutically acceptable salts thereof, whereinAr represents a radical of the formula ##STR4## Wherein in group A R₁ isH, or C₁₋₆ alkyl, and R₂ is H, or halogen;

In group B, K is N or CR₄, L is N or CR₅, R₂ & R₃ are independently H orhalogen, R₄ is H, or C₁₋₆ alkoxy and R₅ is H, halogen, CF₃, C₁₋₆ alkyl,C₁₋₆ alkoxy, C₁₋₆ alkythio, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylsulfinyl, C₁₋₇acyl, cyano, C₁₋₆ alkoxycarbonyl, C₁₋₇ acylamino, hydroxy, nitro, amino,aminocarbonyl, or aminosulfonyl optionally N-substituted by one or twogroups selected from C₁₋₆ alkyl, C₃₋₈ cycloalkyl, and C₃₋₈cycloalkylC₁₋₄ alkyl or disubstituted by C₄ or C₅ polymethylene; phenylor phenyl C₁₋₄ alkyl group optionally substituted in the phenyl ring byone or two of halogen, C₁₋₆ alkoxy or C₁₋₆ alkyl groups;

In group C, M is N or CR₄, R₂ & R₃ are independently H or halogen, R₄ isH or C₁₋₆ alkoxy and R₅ is H, halogen, CF₃, C₁₋₆ alkyl, C₁₋₆ alkoxy,C₁₋₆ alkylthio, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylsulfinyl, C₁₋₇ acyl,cyano, C₁₋₆ alkoxycarbonyl, C₁₋₇ acylamino, hydroxy, nitro, amino,aminocarbonyl, or aminosulfonyl optionally N-substituted by one or twogroups selected from C₁₋₆ alkyl, C₃₋₈ cycloalkyl, and C₃₋₈cycloalkylC₁₋₄ alkyl or disubstituted by C₄ or C₅ polymethylene, phenylor phenyl C₁₋₄ alkyl group optionally the phenyl ring by one or two ofhalogen, C₁₋₆ alkoxy or C₁₋₆ alkyl groups;

In group D one of R₆ and R₇ is C₁₋₆ alkyl and the other is C₁₋₆ alkyl,phenyl or phenyl C₁₋₄ alkyl optionally substituted in either phenyl ringby one or two of C₁₋₆ alkyl, C₁₋₆ alkoxy, or halogen, or R₆ & R₇together are C₂₋₆ polymethylene or C₂₋₅ polymethylene interrupted by an--O--linkage, and R₂ & R₃ are independently H or halogen;

In group E, R₄ is H or C₁₋₆ alkoxy, R₅ is H or C₁₋₆ alkoxy, and R₂ is H,halogen, CF₃, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ alkylthio, C₁₋₆alkylsulfonyl, C₁₋₆ alkylsulfinyl, C₁₋₇ acyl, cyano, C₁₋₆alkoxycarbonyl, C₁₋₇ acylamino, hydroxy, nitro, amino, aminocarbonyl, oraminosulfonyl, optionally N-substituted by one or two groups selectedfrom C₁₋₆ alkyl, C₃₋₈ cycloalkyl, and C₃₋₈ cycloalkylC₁₋₄ alkyl ordisubstituted by C₄ or C₅ polymethylene, phenyl or phenyl C₁₋₄ alkylgroup optionally substituted in the phenyl ring by one or two ofhalogen, C₁₋₆ alkoxy or C₁₋₆ alkyl groups, and R₂ & R₃ are independentlyH or halogen;

In group F, R₁ is H or C₁₋₆ alkyl, and R₂ is H or halogen; and

In group H R₁₅ & R₁₆ are independently H or --CH═CH--CH═CH--;

Y represents NH or 0; and

Z represents a radical of the formula ##STR5## Wherein in group Z₁ m is1 or 2;

In group Z₂ n and p are independently 1 or 2 and o is 0, 1, or

2 such that n+p+o≧3, and R'₁ and R'₂ are independently H, C₁₋₆ alkyl,phenyl or phenyl-C₁₋₆ alkyl, which phenyl moieties may be substituted byC₁₋₆ alkyl, C₁₋₆ alkoxy, or halogen;

In group Z₃ k is 0 to 2, 1 is 0 to 3, j is 0 to 4, and one of R'₃ andR'₄ is H, C₁₋₆ alkyl, phenyl, or phenyl-C₁₋₃ alkyl, which phenylmoieties may be optionally substituted by C₁₋₆ alkyl, C₁₋₆ alkoxy, CF₃or halogen, and the other of R'₃ and R'₄ is H or C₁₋₆ alkyl;

In group Z₄ a is 0 or 1;

In group Z₇ d is 0 or 1, and R'₅ is C₁₋₇ alkyl, C₃₋₈ cycloalkyl, C₃₋₈cycloalkyl-C₁₋₂ alkyl, C₂₋₇ alkenyl, C₂₋₇ alkenyl-C₁₋₄ alkyl, orphenyl-C₁₋₆ alkyl.

In group Z₈ d and R'₅ are as previously defined;

In group Z₉ e is 1 or 2, and R'₅ is as previously defined;

In group Z₁₀ R'₅ is as previously defined; and

In group Z₁₂ r is 1 to 4, R'₆ and R'₇ are independently C₁₋₆ alkyl, C₁₋₆alkenyl, or C₁₋₆ alkynyl or together form --(CH₂)s--, wherein s is 3-7and one of the CH₂ units may optionally be replaced by --O--, or NR'₈,wherein R'₈ is H or C₁₋₆ alkyl;

with the proviso that when Ar is group B, C, D or E, then Z cannot beZ₅, Z₇ or Z₉.

The term "cycloalkyl" embraces cyclic radicals having three to about tenring carbon atoms, preferably three to about six carbon atoms, such ascyclopropyl and cyclobutyl. The term "haloalkyl" embraces radicalswherein any one or more of the alkyl carbon atoms is substituted withone or more halo groups, preferably selected from bromo, chloro andfluoro. Specifically embraced by the term "haloalkyl" are monohaloalkyl,dihaloalkyl and polyhaloalkyl groups. A monohaloalkyl group, forexample, may have either a bromo, a chloro, or a fluoro atom within thegroup. Dihaloalkyl and polyhaloalkyl groups may be substituted with twoor more of the same halo groups, or may have a combination of differenthalo groups. A dihaloalkyl group, for example, may have two bromo atoms,such as a dibromomethyl group, or two chloro atoms, such as adichloromethyl group, or one bromo atom and one chloro atom, such as abromochloromethyl group. Examples of a polyhaloalkyl aretrifluoromethyl, 2,2,2-trifluoroethyl, perfluoroethyl and2,2,3,3-tetrafluoropropyl groups. The terms "alkoxy" and "alkoxyalkyl"embrace linear or branched oxy-containing radicals each having alkylportions of one to about ten carbon atoms, such as methoxy group.

Specific examples of alkyl groups are methyl, ethyl, n-propyl,isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl,iso-pentyl, methyl-butyl, dimethylbutyl and neopentyl. Typical alkenyland alkynyl groups may have one unsaturated bond, such as an allylgroup, or may have a plurality or unsaturated bonds, with such pluralityof bonds either adjacent, such as allene-type structures, or inconjugation, or separated by several saturated carbons.

Included within the family of compounds of the described are thetautomeric forms of the described compounds, isomeric forms includingdiastereoisomers and individual enantiomers, and thepharmaceutically-acceptable salts thereof. The term"pharmaceutically-acceptable salts" embraces salts commonly used to formalkali metal salts and to form addition salts of free acids or freebases. Since the compounds contain basic nitrogen atoms, such salts aretypically acid addition salts. The phrase "pharmaceutically-acceptablesalts" is intended to embrace alkyl quaternary ammonium salts andn-oxides. The nature of the salt is not critical, provided that it ispharmaceutically acceptable, and acids which may be employed to formsuch salts are, of course, well known to those skilled in this art.Examples of acids which may be employed to form pharmaceuticallyacceptable acid addition salts include such inorganic acids ashydrochloric acid, sulfuric acid and phosphoric acid, and such organicacids as maleic acid, succinic acid and citric acid. Otherpharmaceutically acceptable salts include salts with alkali metals oralkaline earth metals, such as sodium, potassium, calcium and magnesium,or with organic bases, such as dicyclohexylamine. All of these salts maybe prepared by conventional means by reacting, for example, theappropriate acid or base with the corresponding compound of theinvention.

The compounds that are the subject of the invention herein can beprepared according to the following reaction schemes.

SCHEME 1

The preparation of compounds of formula I wherein the Ar group is A isshown in Scheme I. Compounds of formula I A are prepared starting fromcommercially available 2-aminonicotinic acid 1. Chloroacetaldehyde isreacted with 1 at elevated temperature in an alcoholic solvent(preferably EtOH at reflux) to afford compound 2A, which is converted tothe acid chloride by conventional methods (preferably thionylchloride/chloroform/dimethylformamide at reflux). This acid chloride 2Bis then reacted with the appropriate amine 3 in the presence of atertiary amine (preferably triethylamine) in a polar organic solvent(preferably dimethylformamide) to afford the desired compounds offormula IA. Alternatively, the imidazopyridine carboxylic acid 2A isreacted with the amine 3 using other acid-activating reagents(dicyclohexylcarbodiimide, iso-butylchloroformate, carbonyldiimidazole(CDI), etc.; preferably CDI in dimethylformamide at room temperature) toafford compounds of formula 1A.

Ring halogenated analogs of formula IA' are prepared according to schemeI. 2-Aminonicotinic acid 1 is converted to its methyl ester byconventional means. Treatment of this ester with halogenating reagents(NBS, NCS, C12, t-butylhypochlorite; preferablyt-butylhypochorite/methanol/room temperature) gives rise to the ringhalogenated intermediate 4, which is converted to the imidazopyridinecarboxylic acid ester 5A using conditions described above for thepreparation of 2A. The corresponding imidazopyridine carboxylic acid 5 Bis converted to compounds of formula IA' using reagents and conditionsdescribed above for the preparation of I A from 2A.

SCHEME 2

The preparation of compounds of formulae IB, IC, ID, and IE are shown inscheme 2. In each case, the known acids 10 [EP 0254584A2, J. MedicinalChemistry (1990), 33, 1924], 11 [EP 0289170A2, J. Medicinal Chemistry(1990), 33, 1924], 12 & 13 [EP 0289170A2, J. Medicinal Chemistry (1990),33, 1929] are reacted with the appropriate amine or alcohol underconditions analogous to those described for scheme 1 or as described inEP 0254584A2 and EP 0289170A2.

SCHEME 3

The preparation of compounds of formula IF are shown in scheme 3.2-Aminopyridine 14 is reacted with ethyl bromopyruvate 15 in analcoholic solvent (preferably ethanol) to afford the imidazopyridinecarboxylic acid ester 16A. Hydrolysis of the ester to the acid 16Boccurs under conventional acid-catalyzed conditions. Conversion of 16Bto amides and ester of formula IF is affected by employing one of anumber of acid-activating reagents as sited above [preferablycarbonyldiimidazole (CDI) in dimethylformamide at room temperature].

SCHEME 4

The preparation of compounds of formulae I-G and I-H are shown in Scheme4. The known triazole aldehyde 17 [G. Jones et al., J. Chemical SocietyPerkin I (1981), 78]is oxidized by use of chromium trioxide/sulfuricacid or other conventional oxidizing agents to afford the triazolecarboxylic acid 18. Coupling of 18 with the appropriate amine or alcohol3 using conditions sited above [preferably CDI in dimethylformamide atroom temperature]affords the desired triazoles of formula 1-G.

For preparation of compounds of formula I-H, the known lithiatedcompound 19 [B. Abarca et al, J. Chemical Society Perkin I (1985), 1897]is quenched with carbon dioxide or alkylhaloformate to afford 20B and20A, respectively. 20A is converted to the acid 20B by conventionalacid-catalyzed hydrolysis. Coupling of 20B with the appropriate amine oralcohol 3 is affected by using the conditions sited above [preferablyCDI in dimethylformamide at room temperature] to afford the desired I-H.Alternatively, the appropriate amine 3 is converted to its carbamoylhalide 21 (Q=Cl, Br) or isocyanate 22. The lithiated species 19 isdirectly quenched with 21 or 22 to directly afford I-H (Y=NH).

These examples, as well as all examples herein, are given by way ofillustration only and are not to be construed as limiting the invention,either in spirit or scope, as many modifications, both in materials andmethods, will be apparent from this disclosure to those skilled in theart. In these examples, temperatures are given in degrees Celsius (°C.)and quantities of materials in grams and milliliters unless otherwisenoted. ##STR6##

Example A (Methyl 2-aminonicotinate) ##STR7## Procedure

The 2-aminonicotinic acid (5.0 g, 0.0362 mol) and K₂ CO₃ (5.0 g, 0.0362mol) were suspended in 50 ml of DMF and heated to reflux. Almostcomplete solution occurred. The mixture was cooled to 25° C. and the CH₃I (5.1 g/2.2 ml, 0.0362 mol) was added and the mixture was stirred 18hours. The mixture was filtered and concentrated. The residue was placedon a bed of silica and eluted with 5%/EtOH/CH₂ Cl₂ /1/10% NH₄ OH. Thefractions containing the product were combined and concentrated. Theresidue was suspended in Et₂ O, filtered and washed with Et₂ O to yield3.2 g (58%) the title compound.

    ______________________________________                                        Elements     Calc     Found                                                   ______________________________________                                        Carbon       55.26    54.90   C.sub.7 H.sub.8 N.sub.2 O.sub.2                 Hydrogen      5.30     5.36                                                   Nitrogen     18.41    18.26   MW 152.15                                       ______________________________________                                    

Example B (Methyl 2-amino-5-chloronicotinate) ##STR8## Procedure

The compound of example A (800 mg, 0.00525 mol) was dissolved in MeOH(15 ml) and HCl gas was passed over the solution until the solution wasacidic (pH 2). The solution was concentrated and the residue redissolvedin MeOH (15 ml). The t-butylhypochlorite (570 mg, 0.00525 mol) was addedand the reaction mixture stirred until the yellow color dissipated.Additional t-butylhypochlorite was added until tlc (5% EtOH/CH₂ Cl₂/1/10% NH₄ OH) indicated that the starting material was consumed.

The reaction mixture was concentrated and the residue dissolved in CH₂Cl₂. The organics were washed with 5% NaHCO₃ then 5% sodium thiosulfate.The organic layer was dried over MgSO₄ and concentrated to afford asolid. The solid was suspended in 1:1 CH₂ Cl₂ /hexane, filtered, washedwith hexane and suction dried to yield 250 mg (26%) of the titlecompound m.p. 139°-40° C.

    ______________________________________                                        Elements     Calc     Found                                                   ______________________________________                                        Carbon       45.60    44.72   C.sub.7 H.sub.7 ClN.sub.2 O.sub.2               Hydrogen      3.78     3.75                                                   Nitrogen     15.01    15.00   MW 186.60                                       Chlorine     19.00    19.20                                                   ______________________________________                                    

Example C (6-Chloroimidazo[1,2-a]pyridine-8-carboxylic acid,monohydrochloride) ##STR9## Procedure

The compound of example B (1.2 g, 0.0063 mol) and chloroacetaldehyde[45% aqueous solution (930 mg, 0.007 mol)] was heated to reflux in EtOHuntil tlc (5% EtOH/CH₂ Cl₂ /1/10% NH₄ OH) indicated that the reactionwas complete. The solution was concentrated and the residue wassuspended in acetone, filtered, washed with acetone, and air dried toyield 1.3 g (77%) of the methyl ester of the title compound m.p.148°-150° C. (resolidify) 235°-238° C. (decomp).

    ______________________________________                                        Elements                                                                              Calc    Found                                                         ______________________________________                                        Carbon  40.50   40.58   C.sub.9 H.sub.7 ClN.sub.2 O.sub.2 *1.05                                       HCl*1.0H.sub.2 O                                      Hydrogen                                                                               3.80    3.82                                                         Nitrogen                                                                              10.50   10.53   MW 266.92                                             Chlorine                                                                              27.23   27.43                                                         ______________________________________                                    

The methyl ester was heated to reflux in 15 ml of con HCl until tlc (5%EtOH/CH₂ Cl₂ /1/10% NH₄ OH) indicated that the starting material wasconsumed. Concentration gave a residue which was suspended in acetone,filtered and dried to afford 1.15 g (99%) of the title compound: softens275° C.; m.p. 279°-281° C. (decomp).

    ______________________________________                                        Elements   Calc     Found                                                     ______________________________________                                        Carbon     41.23    40.99    C.sub.8 H.sub.5 ClN.sub.2 O.sub.2 *HCl           Hydrogen    2.60     2.53                                                     Nitrogen   12.02    11.95    MW 233.05                                        Chlorine   30.42    30.52                                                     ______________________________________                                    

Example D (Imidazo[1,2-a]pyridine-8-carboxylic acid, monohydrochloride)##STR10## Procedure

Using 2-aminonicotinic acid (14.1 g, 0.102 mol) and chloroacetaldehyde[45% aqueous solution (8.6 g, 0.11 mol)], the same procedure asdescribed above in example C was used. After workup 17.5 g (88%) of thetitle compound, m.p. 299°-300° C. (decomp), was isolated.

    ______________________________________                                        Elements   Calc    Found                                                      ______________________________________                                        Carbon     48.38   48.16    C.sub.9 H.sub.7 ClN.sub.2 O.sub.2 *1 HCl          Hydrogen    3.55    3.59                                                      Nitrogen   14.10   13.95    MW 198.61                                         Chlorine   17.85   17.50                                                      ______________________________________                                    

Example E (Imidazo[1,2-a]pyridine-2-carboxylic acid monohydrochloride)##STR11## Procedure

2-aminopyridine (25.0 g, 0.128 mol) and ethyl bromopyruvate (12.0 g,0.128 mol) were heated to reflux in EtOH (225 ml). The reaction mixturewas concentrated and the residue partitioned between dilute K₂ CO₃ andCH₂ Cl₂. The organic layer was passed through a small bed of silica,eluting with 0.5% EtOH/CH₂ Cl₂. The product eluted at the solvent frontand this fraction was concentrated. The solid residue was suspended inEt₂ O then filtered to yield 10.9 g (44%) of the ethyl ester of thetitle compound.

    ______________________________________                                        Elements   Calc    Found                                                      ______________________________________                                        Carbon     62.56   62.79    C.sub.10 H.sub.10 N.sub.2 O.sub.2 *.1 H.sub.2                                 O                                                 Hydrogen    5.35    5.33                                                      Nitrogen   14.59   14.62    MW 192.00                                         ______________________________________                                    

The ethyl ester (5.0 g, 0.0256 moles) was refluxed in 50 ml of con HCluntil tlc (5% EtOH/CH₂ Cl₂ /1/10% NH₄ OH) indicated that the startingmaterial was consumed. Concentration gave a residue which was suspendedin acetone, filtered and dried to afford 5.2 g (95%) of the titlecompound.

    ______________________________________                                        Elements    Calc     Found                                                    ______________________________________                                        Carbon      44.36    44.23     C.sub.8 H.sub.6 N.sub.2 O.sub.2 *HCl           Hydrogen     4.19     4.17                                                    Nitrogen    12.93    12.77     MW 216.62                                      Chlorine    16.37    16.45                                                    ______________________________________                                    

EXAMPLE 1(endo-N-(1-Azabicyclo[3.3.1]nonan-4-yl)-6-chloroimidazo[1,2-a]pyridine-8-carboxamide,dihydrochloride) ##STR12## Procedure

The compound of example C (1.1 g, 0.0047 mol) was suspended in CHCl₃/DMF (25 ml/3 drops). SOCl₂ (560 mg/0.338 ml, 0.0047 mol) was added andthe mixture was heated to reflux with additional SOCl₂ added until tlc(5% EtOH/CH₂ Cl₂ /1/10% NH₄ OH) indicated that the starting material wasconsumed. The mixture was concentrated in vacuo, azeotroping once withtoluene.

To the residue, dissolved in DMF (15 ml) and cooled in an ice bath, wasadded Et₃ N (1.19 g/1.64 ml, 0.0118 mol) followed byendo-4-amino-l-azabicyclo[3.3.1]nonane (649 mg, 0.0047 mol) dissolved in5 ml of DMF. The mixture was warmed to room temperature and stirred for4 hours. Tlc (10% EtOH/CH₂ Cl₂ /1/10% NH₄ OH) on basic alumnia indicatedthat the acid chloride was consumed. Concentration afforded a residuewhich was chromatographed on basic alumnia eluting with 1% EtOH/CH₂ Cl₂/1/10% NH₄ OH. The fractions containing the product were combined andconcentrated in vacuo.

The residue was converted to the hydrochloride salt by dissolving iniPrOH and passing HCl gas over the solution. The solid was filtered,washed with iPrOH and dried in a vacuum desicator to yield 445 mg (20%)of the title compound, softens 230° C.; m.p. 264°-266° C. (decomp).

    ______________________________________                                        Elements                                                                              Calc    Found                                                         ______________________________________                                        Carbon  43.72   43.57   C.sub.16 H.sub.19 ClN.sub.4 O *2.6 HCl*2.0H.sub.2                             O                                                                             *0.45 iPrOH                                           Hydrogen                                                                               6.17    5.80                                                         Nitrogen                                                                              11.58   11.40   MW 476.68                                             Chlorine                                                                              26.77   26.52                                                         ______________________________________                                    

EXAMPLE 2(endo-N-(1-Azabicyclo[3.3.1]nonan-4-yl)imidazo[1,2-a]pyridine-8-carboxamide,dihydrochloride) ##STR13## Procedure

Employing the compound of example D (1.4 g, 0.0071 mol), SOCl₂ (2.3g/1.4ml, 0.02 mol), endo-4-amino-1-azabicyclo[3.3.1]nonane (1.0 g,0.00713 mol), and Et₃ N (2.5 g/3.84 ml, 0.0249 mo) dissolved in CHCl₃/DMF (25 ml/3 drops), the same procedure as described in example 1 wasused. After workup 121 mg (5%) of the title compound was isolated.

    ______________________________________                                        Elements Calc    Found                                                        ______________________________________                                        Carbon   51.65   51.43    C.sub.15 H.sub.20 N.sub.4 O                                                   *2 HCl*1/3H.sub.2 O*0.25 iPrOH                      Hydrogen  6.79    6.38                                                        Nitrogen 15.30   15.12    MW 366.24                                           Chlorine 19.36   19.26                                                        ______________________________________                                    

EXAMPLE 3(endo-N-(8-Methyl-8-azabicyclo[3.2.11octan-3-yl)-6-chloroimidazo[1,2-a]pyridine-8-carboxamide,dihydrochloride) ##STR14## Procedure

The compound of example C (233 mg, 0.001 mol) and1,1'-carbonyldiimidazole (241 mg, 0.0015 moles) were suspended DMF (5ml) and the mixture was stirred until solution occurred (three hours).Endo-N-8-methyl-8-azabicyclo[3.2..1]-octane-3-amine [produced inaccordance with the procedure in J. Am. Chem. Soc. 79, 4194(1957)] wasadded and the mixture was stirred for 18 hours. Tlc (30% EtOH/CH₂ Cl₂/1/10% NH₄ OH) indicated that the reaction was complete. Concentrationafforded a residue which was purified by radial chromatography [(2 mmplate), gradient elution with 25% 75% i-PrOH/CH₂ Cl₂ /1/10% NH₄ OH].Three components were collected. The desired was found in thethird-eluted component. Concentration afforded a residue which wasconverted to the hydrochloride salt by dissolving in and passing HCl gasover the solution. The solid was filtered, washed with iPrOH and driedin a vacuum desicator to yield 113 mg (25%) of the title compound.

    ______________________________________                                        Elements Calc    Found                                                        ______________________________________                                        Carbon   48.17   47.77    C.sub.16 H.sub.19 ClN.sub.4 O                                                 *2 HCl *H.sub.2 O *0.75 iPrOH                       Hydrogen  6.43    6.36                                                        Nitrogen 12.32   11.98    MW 454.82                                           Chlorine 23.38   23.18                                                        ______________________________________                                    

EXAMPLE 4(endo-N-(8-methyl-8-azabicyclo[3.2.11octan-3yl)imidazo[1,2-a]pyridine-8-carboxamide,hydrochloride) ##STR15## Procedure

The compound of example D (200 mg, 0.00101 mol) and1,1'-carbonyldiimidazole (164 mg, 0.00101 mol) were suspended in the DMF(2 ml) and the mixture was stirred until solution occurred (2.5 hours),Endo-N-8-methyl-8-azabicyclo[3.2.1]-octane-3-amine was added and themixture was stirred for 48 hours. The mixture was concentrated to onehalf the original volume and EtOAc (2 ml) was added. The solid wasfiltered to afford (126 mg, 39%) the title compound.

    ______________________________________                                        Elements                                                                              Calc    Found                                                         ______________________________________                                        Carbon  58.26   58.00   C.sub.16 H.sub.20 N.sub.4 O*1.1 HCl*0.3H.sub.2 O      Hydrogen                                                                               6.63    6.65                                                         Nitrogen                                                                              16.99   17.02   MW 329.67                                             Chlorine                                                                              11.82   11.90                                                         ______________________________________                                    

MS calcd for C₁₆ H₂₀ N₄ O284.1637; found 284.1640.

EXAMPLE 5 (exo-N-(8-methyl-8-azabicyclo[3.2-11octan-3yl) imidazo[1,2-a]pyridine-8-carboxamide, hydrochloride) ##STR16## Procedure

The compound of example D (200 mg, 0.00101 mol) and1,1'-carbonyldiimidazole (164 mg, 0.00101 mol) were suspended in DMF (2ml) and the mixture was stirred until solution occurred (2.5 hours).Exo-N-8-methyl-8azabicyclo[3.2.1]octane-3-amine [prepared in accordancewith the procedure in Berichte 31, 1202(1898)] was added to the mixtureand the resulting suspension was stirred for 4 days. EtOAc was added tothe mixture and the solid filtered to afford (282 mg, 76%) the titlecompound.

    ______________________________________                                        Elements   Calc     Found                                                     ______________________________________                                        Carbon     59.23    59.30    C.sub.16 H.sub.20 N.sub.4 O*1.1 HCl              Hydrogen    6.56     6.71                                                     Nitrogen   17.24    17.33    MW 324.47                                        Chlorine   12.02    11.85                                                     ______________________________________                                    

MS calcd for C₁₆ H₂₀ N₄ O284.1637; found 284.1643.

EXAMPLE 6(endo-N-(9-Methyl-9-azabicyclo[3.3.1]nonan-3-yl)-6-chloroimidazo[1,2-a]pyridine-8-carboxamide hydrochloride) ##STR17## Procedure

The compound of example C (233 mg, 0.001 mol) and1,1'-carbonyldiimidazole (178 mg, 0,001 mol) were suspended in DMF (5ml), and the mixture was stirred for one hour before addingendo-N-9-methyl-9-azabicyclo[3.3.1]-nonane-3-amine (154 mg, 0.0011moles), The mixture was stirred for 18 hours. TIc (30% EtOH/CH₂ Cl₂/1/10% NH₄ OH) indicated that the reaction was complete. Concentrationafforded a residue which was suspended in water and the pH adjusted to11 with K₂ CO₃. The solid was filtered and purified by radialchromatography [(2 mm plate), gradient elution 25% to 75% i-PrOH/CH₂ Cl₂/1/10% NH₄ OH]. Two components were collected. The desired product wasfound in the second-eluted component. Concentration afforded a residuewhich was converted to the hydrochloride salt by dissolving the residuein iPrOH then acetone and passing HCl gas over the solution. The solidwas filtered, washed with i-PrOH then acetone and dried in a vacuumdesicator to yield 168 mg (32%) of the title compound.

    ______________________________________                                        Elements   Calc    Found                                                      ______________________________________                                        Carbon     45.57   45.36    C.sub.17 H.sub.21 CIN.sub.4 O * 2.5 HCl                                       * 2.5 H.sub.2 O * acetone                         Hydrogen    6.60    6.68                                                      Nitrogen   10.63   10.61    MW 527.106                                        Chlorine   23.54   23.67                                                      ______________________________________                                    

EXAMPLE 6A(endo-N-(9-Methyl-9-azabicyclo[3.3.1]nonan-3-Yl)-imdazo[1,2a]pyridine-8-carboxamide)##STR18## Procedure

The compound of Example D (198 mg, 0.001 moles) and1,1'-carbonyldi-imidazole (178 mg, 0.001 moles) were suspended in theDMF (5 ml) and the mixture was stirred until solution occurred (threehours). Endo-N-8-methyl-8-azabicyclo[3.2.1]-octane-4-amine andtriethylamine (560 μl; 0.004 mole) were added and the mixture wasstirred for 18 hours. Tlc 30% EtOH/CH₂ Cl₂ /1/10% NH₄ OH indicated thatthe reaction was complete. Concentration afforded a residue which waspurified by radial chromatography (2 mm plate), gradient elution with200 ml portions of 10% i-prOH/CH₂ Cl₂ /1/10% NH₄ OH, 15, 20% i-PrOH(iso-propylalcohol). Three components were collected. The desired wasfound in the third component. Concentration afforded a residue which wasconverted to the hydrochloride salt by dissolving the residue in i-PrOHand passing HCl gas over the solution. The solid was filtered, washedwith i-PrOH and dried in a vacuum desicator to yield 133 mg (44.6%) ofthe title compound.

    ______________________________________                                        Elements Calc    Found                                                        ______________________________________                                        Carbon   53.45   53.75    C.sub.17 H.sub.22 N.sub.4 O                                                   * 2.05 HCl *0.2 iPrOH                               Hydrogen  6.93    6.59                                                        Nitrogen 15.01   14.79    MW 373.14                                           Chlorine 19.48   19.63                                                        ______________________________________                                    

EXAMPLE 7(N-(1-Azabicyclo[2.2.2]octan-3-yl)-6-chloroimidazo[1,2-a]pyridine-8-carboxamidedihydrochloride) ##STR19## Procedure

Using the compound of example C (233 mg, 0,001 moles),1,1'-carbonyldiimidazole (241 mg, 0.0015 moles), and 3-aminoquinuclidinedihydrochloride (280 mg, 0.002 moles) in DMF (5 ml) the coupling wasperformed as described in example 3.

The residue was partitioned between dilute K₂ CO₃ and CH₂ Cl₂. Theorganic layer was separated, dried over MgSO₄ and concentrated to affordto an oil. The oil was purified by silica gel chromatography [gradientelution with 20% to 100% iPrOH/CH₂ Cl₂ /1/10% NH₄ OH]. The fractionscontaining the desired product were combined and concentrated to an oilwhich crystallized. The solid residue was converted to the hydrochloridesalt by dissolving the residue in iPrOH and passing HCl gas over thesolution. The solid was filtered, washed with iPrOH and dried in avacuum desicator to yield 221 mg (56%) of the title compound.

    ______________________________________                                        Elements Calc    Found                                                        ______________________________________                                        Carbon   45.55   45.95    C.sub.15 H.sub.17 ClN.sub.4 O *2 HCl *H.sub.2                                 O                                                   Hydrogen  5.35    5.13                                                        Nitrogen 14.16   14.45    MW 395.72                                           Chlorine 26.88   27.11                                                        ______________________________________                                    

EXAMPLE 8(N-(1-Azabicyclo[2.2.2]octan-3-yl)imidazo[1,2-a]pyridine-8-carboxamide,dihydrochloride) ##STR20## Procedure

Employing the compound of example D (1.98 g, 0.01 mol), SOCl₂ (2.3g/1.4ml, 0.02 mol), 3-aminoquinuclidine dihydrochloride (200 mg, 0.01mol), and Et₃ N (4.0 g/5.6 ml, 0.04 mol) dissolved in CHCl₃ /DMF (25ml/3 drops) the same procedure as described in example 1 was used. Afterworkup 2.2 mg (59%) of the title compound was isolated, m.p. 222° C.(softens); 241°-245° C. (decomposes).

    ______________________________________                                        Elements   Calc    Found                                                      ______________________________________                                        Carbon     50.88   50.73    C.sub.15 H.sub.218 N.sub.4 O *2 HCl                                           *0.25H.sub.2 O*0.75 iPrOH                         Hydrogen    6.37    6.06                                                      Nitrogen   15.07   15.40    MW 371.79                                         Chlorine   19.07   18.83                                                      ______________________________________                                    

EXAMPLE 9((±)-endo-N-(Hexahydro-1H-2,5β-methano-3aα,6aα-cyclopenta[c]pyrrol-4α-yl)-6-chloroimidazo[1,2-a]pyridine-8-carboxamide,monohydrochloride) ##STR21## Procedure

The compound of example C (115 mg, 0.0005 mol) and1,1'-carbonyldiimidazole (86 mg, 0.000525 mol) were suspended in DMF(2.5 ml ), and the mixture was stirred for one hour before adding(±)-endo-N-hexahydro-1H-2,5β-methano-3aα,6aα-cyclopenta[c]pyrrol-4α-amine[U.S. patent appl. Ser. No. 07/515,391] (69 mg, 0.0005 mol). A solidprecipitated from solution. The mixture was stirred for an additionalhour. The solid was filtered, washed with acetone, and dried to yield 97mg (52%) of the title compound.

    ______________________________________                                        Elements Calc    Found                                                        ______________________________________                                        Carbon   51.76   51.81    C.sub.16 H.sub.17 ClN.sub.4 O *HCl *H.sub.2 O       Hydrogen  5.43    5.24                                                        Nitrogen 15.09   15.27    MW 371.27                                           Chlorine 19.10   19.47                                                        ______________________________________                                    

EXAMPLE 10((±)-endo-N-(Hexahydro-1H-2,5β-methano-3aα,6aα-cyclopenta[c]pyrrol-4α-yl)imidazo[1,2-a]pyridine-8-carboxamide,hydrochloride) ##STR22## Procedure

The compound of example D (53 mg, 0.00027 mol) and1,1'-carbonyldiimidazole (43 mg, 0.00027 mol) were suspended in DMF (2ml), and the suspension was stirred for 4.5 h.(±)-Endo-N-hexahydro-1H-2,5β-methano-3aα,6aα-cyclopenta[c]pyrrol-4α-aminewas added and the mixture was stirred for 16 h. The mixture was dilutedwith EtOAc and the solid filtered to afford (46 mg, 58%) the titlecompound.

    ______________________________________                                        Elements   Calc     Found                                                     ______________________________________                                        Carbon     58.28    58.17    C.sub.16 H.sub.18 N.sub.4 O*1.3HCl               Hydrogen    5.90     5.97                                                     Nitrogen   16.99    17.04    MW 329.54                                        ______________________________________                                    

MS calcd for C₁₆ H₂₁₈ N₄ O 282.1480; found 282.1472.

EXAMPLE 11 (exo-N-(1-azatricyclo[3.3.1.1³,7]decan-4-yl)-6-chloroimidazo[1,2-a]pyridine-8-carboxamide,monohydrochloride) ##STR23## Procedure

The compound of example C (150 mg, 0.00064 mol) and1,1'-carbonyldiimidazole (104 mg, 0.00064 mol) were suspended in DMF (1ml), and the suspension was stirred for 2 h. A solution ofexo-N-(1-azatricyclo[3.3.1.1³,7 ]decane-4-amine in DMF (1 ml) was addedand the mixture was stirred for 16 h. The mixture was diluted with EtOAc(4 ml). The solid was filtered to afford 226 mg of a solid which wasrecrystallized from MeOH to yield (139 mg, 59%) the title compound.

    ______________________________________                                        Elements   Calc     Found                                                     ______________________________________                                        Carbon     55.60    55.20    C.sub.17 H.sub.19 ClN.sub.4 O *1 HCl             Hydrogen    5.49     5.51                                                     Nitrogen   15.41    15.26    MW 367.26                                        Chlorine   19.31    19.59                                                     ______________________________________                                    

EXAMPLE 11A (1α, 3β, 5α, 7β-1-azatricyclo[3.3.1.1³,7]decan-4β-7yl)-6-chloroimidazo[1,2-a]pyridine-8-carboxamidedihydrochloride ##STR24## Procedure

The compound of Example C (153 mg, 0.00065 moles) and1,1'-carbonyldi-imidazole (106 mg, 0.00065 moles) were suspended in theDMF (2.5 ml) and the mixture was stirred until solution occurred (threehours). At this time, 1α,3β,5α,7β-1-azatricyclo[3.3.1.1³,7]decan-4β-amine and triethylamine (280 μl; 0.002 mole) were added andthe mixture was stirred for 18 hours. Tlc 30% EtOH/CH₂ Cl₂ /1/10% NH₄ OHindicated that the reaction was complete. Concentration afforded aresidue which was partitioned between dilute K₂ CO₃ and CHCl₃. Theorganic layer was dried over MgSO₄ and concentrated. The residue wasrecrystallized from i-PrOH/HCl. The solid was filtered, washed withi-PrOH and dried in a vacuum desicator to yield 113 mg (39%) of thetitle compound.

    ______________________________________                                        Elements   Calc    Found                                                      ______________________________________                                        Carbon     49.68   49.97    C.sub.17 H.sub.19 ClN.sub.4 O*2HCl                                            *0.75 H.sub.2 O *0.5 i-PrOH                       Hydrogen    5.97    5.84                                                      Nitrogen   12.53   12.39    MW 447.30                                         Chlorine   23.78   23.78                                                      ______________________________________                                    

EXAMPLE 12(N-[2-(Diethylamino)ethyl]imidazo[1,2-a]pyridine-8-carboxamide)##STR25## Procedure

Employing the compound of example D (1.98 g, 0.01 mol), SOCl₂ (2.3 g/1.4ml, 0.02 mol), N,N-diethylenediamine (1.27 g, 0.011 mol), and Et₃ N (2.0g/2.8 ml, 0.02 mol) dissolved in CHCl₃ /DMF (25 ml/3 drops), the sameprocedure as described in example 1 was used. After workup 610 mg (23%)of the title compound was isolated as an oil.

    ______________________________________                                        Elements   Calc   Found                                                       ______________________________________                                        Carbon     63.49  63.54       C.sub.14 H.sub.20 N.sub.4 O *.25H.sub.2 O       Hydrogen   7.80   7.55                                                        Nitrogen   21.16  20.99       MW 264.83                                       ______________________________________                                    

EXAMPLE 13(Cis-N-[[3-(4-Fluorophenoxy)propyl]-3-methoxy-4-piperidinylamine]imidazo[1,2-a]pyridine-8-carboxamide) ##STR26## Procedure

Employing the compound of example D (1.98 g, 0.01 mol), SOCl₂ (2.3 g/1.4ml, 0.02 mol),cis-1-[3-(4-fluorophenoxy)propyl]-3-methoxy-4-piperidinylamine (3.1 g,0.011 mol), and Et₃ N (3.5 g/3.84 ml, 0.035 mol) dissolved in CHCl₃ /DMF(25 ml/3 drops), the same procedure as described in example 1 was used.After workup 2.29 mg (42%) of the title compound was isolated.

    ______________________________________                                        Elements                                                                              Calc    Found                                                         ______________________________________                                        Carbon  50.64   50.74   C.sub.23 H.sub.29 FN.sub.4 O.sub.3 *2.4 HCl                                   *1.75H.sub.2 O                                        Hydrogen                                                                              6.08    5.69                                                          Nitrogen                                                                              10.27   10.44   MW 545.53                                             Chlorine                                                                              15.60   15.44                                                         ______________________________________                                    

EXAMPLE 14(N-[1-(Phenylmethyl)-4-piperidinyl]imidazo[1,2-a]pyridine-8-carboxamide,dihydrochloride) ##STR27## Procedure

Employing the compound of example D (1.98 g, 0.01 moles), SOCl₂ (2.3g/1.4 ml, 0.02 mol), 4-amino-1-benzylpiperidine (2.0 g, 0.011 mol), andEt₃ N (3.5 g/4.89 ml, 0.035 mol) dissolved in CHCl₃ /DMF (25 ml/3drops), the same procedure as described in example 1 was used. Afterworkup 3.1 g (72%) of the title compound was isolated, m.p. 290°-291° C.(decomposes).

    ______________________________________                                        Elements Calc    Found                                                        ______________________________________                                        Carbon   56.01   56.32    C.sub.20 H.sub.22 N.sub.4 O.sub.3 *2 HCl                                      *.5H.sub.2 O                                        Hydrogen 5.99    5.94                                                         Nitrogen 13.06   12.67    MW 383.92                                           Chlorine 16.53   16.54                                                        ______________________________________                                    

EXAMPLE 14AN-exo((4-s,7α-s)-tetrahydro-1H-pyrrolizin-4(5H)-yl)-6-chloroimidazo[1,2-a]pyridine-8-carboxamidedihydrochloride ##STR28## Procedure

The acid of the compound of Example B (118 mg, 0.00051 moles) and1,1'-carbonyldi-imidazole (70 mg, 0.00051 moles) were suspended in theDMF (1 ml) and the mixture was stirred until solution occurred (threehours). At this time, exo(4-s,7α-s)-tetrahydro-1H-pyrrolizin-4-amine (70mg; 0.000499 moles) and triethylamine (280 μl; 0.002 mole) were addedand the mixture was stirred for 18 hours. Tlc 30% EtOH/CH₂ Cl₂ /1/10%NH₄ OH indicated that the reaction was complete. Concentration affordeda residue which was purified by prep tlc chromatography, elution with30% MeOH/CH₂ Cl₂ /1/10% NH₄ OH to yield 182 mg (90%) of the pyridinederivative.

This compound (120 mg; 0.00045 moles) was combined withchloroacetaldehyde (45% in H₂ O)(142mg; 0.0009 moles) in EtOH (10 ml)and refluxed until tlc 30% EtOH/CH₂ Cl₂ /1/10% NH₄ OH indicated that thereaction was complete. Concentration afforded a residue which waspurified by prep tlc chromatography, elution with 30% MeOH/CH₂ Cl₂/1/10% NH₄ OH to yield 105 mg (73%) of the product. The residue wasconverted to the HCl salt with MeOH/HCl.

    ______________________________________                                        Elements                                                                              Calc   Found                                                          ______________________________________                                        Carbon  42.24  42.43   C.sub.15 H.sub.18 ClN.sub.4 O*2.35 HCl*2.75                                   H.sub.2 O                                                                     0.25 MeOH                                              Hydrogen                                                                              6.08   6.01                                                           Nitrogen                                                                              12.13  12.13   MW 462.04                                              Chlorine                                                                              25.70  25.72                                                          ______________________________________                                    

EXAMPLE 14BN-exo(tetrahydro-1H-pyrrolizin-4(5H)-Yl)-6-chloroimidazo[1,2-a]pyridine-8-carboxamidedihydrochloride ##STR29## Procedure

The compound of Example D (198 mg, 0.001 moles) and1,1'-carbonyldi-imidazole (178 mg, 0.0011 moles) were suspended in theDMF (5 ml) and the mixture was stirred until solution occurred (threehours). At this time, exotetrahydro-1H-pyrrolizin-4(5H)-amine andtriethylamine (560 μl; 0.004 mole) were added and the mixture wasstirred for 18 hours. Tlc 30% EtOH/CH₂ Cl₂ /1/10% NH₄ OH indicated thatthe reaction was complete. Concentration afforded a residue which waspartitioned between dilute K₂ CO₃ and CHCl₃. The organic layer was driedover MgSO₄ and concentrated. The residue was recrystallized fromi-PrOH/HCl. The solid was filtered, washed with i-PrOH and dried in avacuum desicator to yield 244 mg (60%) of the title compound.

    ______________________________________                                        Elements                                                                              Calc    Found                                                         ______________________________________                                        Carbon  47.24   47.58   C.sub.15 H.sub.17 ClN.sub.4 O * 2 HCl *0.50                                   H.sub.2 O                                                                     *0.33 i-PrOH                                          Hydrogen                                                                              5.61    5.47                                                          Nitrogen                                                                              13.78   13.60   MW 406.54                                             Chlorine                                                                              26.16   26.03                                                         ______________________________________                                    

EXAMPLE 14CN-exo(tetrahydro-1H-pyrrolizin-4(5H)-yl)imidazo[1,2-a]pyridine-8-carboxamidedihydrochloride ##STR30## Procedure

The compound of Example D (233 mg, 0.001 moles) and1,1'-carbonyldi-imidazole (178 mg, 0.0011 moles) were suspended in theDMF (5 ml) and the mixture was stirred until solution occurred (threehours). Exo-tetrahydro-1H-pyrrolizin-4(5H)-amine and triethylamine (560μl; 0.004 mole) were added and the mixture was stirred for 18 hours. Tlc30% EtOH/CH₂ Cl₂ /1/10% NH₄ OH indicated that the reaction was complete.Concentration afforded a residue which was purified by radialchromatography (2 mm plate), gradient elution with 200 ml portions of10% i-PrOH/CH₂ Cl_(2/1/10) % NH₄ OH, 15, 20% i-PrOH. The residue wascrystallized from i-PrOH/HCl. The solid was filtered, washed with i-PrOHand dried in a vacuum desicator to yield 176 mg (48%) of the titlecompound.

    ______________________________________                                        Elements Calc    Found                                                        ______________________________________                                        Carbon   49.62   49.23    C.sub.15 H.sub.18 N.sub.4 O * 2.05 HCl *H.sub.2                               O                                                   Hydrogen 6.12    6.11                                                         Nitrogen 15.43   15.33    MW 363.10                                           Chlorine 20.02   19.94                                                        ______________________________________                                    

EXAMPLE 15((±)-endo-N-(Hexahydro-1H-2,5β-methano-3aα,6aα-cyclopenta[c]pyrrol-4aα-yl)-3-ethylindolizine-1-carboxamidemonohydrochloride) ##STR31## Procedure

3-Ethylindolizine-l-carboxylic acid (76.7 mg, 0.000405 mol) [preparationdescribed by Bermudez et al. in Journal of Medicinal Chemistry (1990)33:1928] and 1,1'-carbonyldiimidazole (65.7 mg, 0.000405 mol) weresuspended in DMF (5 ml) and the mixture was stirred for 4 h.(±)-Endo-N-(Hexahydro-1H-2,5β-methano-3aα,6aα-cyclopenta[c]pyrrol-4α-amine(56 mg, 0.000405 mol) in DMF (1 ml) was added and the mixture stirred anadditional 22 h. An additional premixed portion of3-ethylindolizine-1-carboxylic acid (38 mg, 0.20 mmol) and1,1'-carbonyldiimidazole (33 mg, 0.20 mmol) in DMF (1 ml) was added.This mixture was stirred for an additional 16 h. The reaction mixturewas concentrated in vacuo to give a residue which was treated with 20%K₂ CO₃ (1 ml) and extracted with CHCl₃ (3X). The combined extracts werewashed with water and brine and dried over Na₂ SO₄. Concentration invacuo gave 74 mg of an oil which was chromatographed on silica geleluting with 3/97 MeOH(NH₃)/CHCl₃ to give the desired amide (21.4 mg,17%) as the free base. The free base was converted to the hydrochloridesalt by dissolving in HCl/MeOH [prepared from acetyl chloride (4.9 μl,0.069 mmol) and MeOH (1 ml)]. Concentration in vacuo gave the desiredhydrochloride salt (24.2 mg) as a solid.

    ______________________________________                                        Elements Calc    Found                                                        ______________________________________                                        Carbon   60.61   60.55    C.sub.19 H.sub.23 N.sub.3 O *1.1 HCl                                          *1.5H.sub.2 O                                       Hydrogen 7.25    6.80                                                         Nitrogen 11.16   11.06    MW 376.31                                           ______________________________________                                    

MS calcd for C₁₉ H₂₃ N₃ O: 309.1841; found 309.1845.

EXAMPLE 15A (1α, 3β, 5α, 7β-1-azatricyclo[3.3.1.1³,7]decan-4β-yl)-3-ethylindolizine-1-carboxamide monohydrochloride##STR32## Procedure

3-ethylindolizine-1-carboxylic acid (190 mg, 1.0 mmole) was dissolved inCHCl₃ (dry), oxalyl chloride (184 μl, 2.1 mmole) was added and themixture stirred for 2 hours. Concentration in vacuo gave a solid, whichwas redissolved in CHCl₃ (5 ml)/DMF (0.3 mls). A solution ofendo-N-(1-azatricyclo[3.3.1.1.]decane-4 amine (140 mg, 0.92 mmole),triethyl amine [280 μl, 2.0 mmole) in CHCl₃ (2 ml) was added. Themixture was stirred for 18 hours. The organic layer was washed with 1NNaOH, brine and dried over K₂ CO₃. Filtration and concentration in vacuoafforded 0.420 mg of a solid which was chromatographed on silica geleluting with 8% CH₃ OH (NH₃ )/CHCl₃ to give the title compound (197 mg,66%) as the free base.

Calculated MS for C₂₀ H₂₅ N₃ O: 323.20

Found: 323. 199 DSC=188.12°-191.72° C. @82.5 5/g.

And: Calculated for C₂₀ H₂₅ N₃ O·2H₂ O: C, 73.45; H, 7.83; N, 12.85

Found: C, 73.32; H, 7.80; N, 12.70

The HCl salt was made by adding acetyl chloride (87 μl, 1.22 mmole) toCH₃ OH (1 ml) stirring for 25 minutes, and addition of the free base(197 mg, 0.609 mole). The solution was stirred 1 hour. Concentration invacuo to about 0.4 ml and addition of Et₂ O (200 ml) gave a solid wasfiltered and dried under vacuum to yield 182 mg (83%) of the titlecompound.

    ______________________________________                                        Calculated for C.sub.20 H.sub.25 N.sub.3 O.HCL.4H.sub.2 O:                                            Found                                                 ______________________________________                                        C,            65.44         65.66                                             H,             7.36         7.20                                              N,            11.45         11.21                                             Cl,           9.66          9.91                                              ______________________________________                                    

Calculated HRMS for C₂₀ H₂₅ N₃ O=323.42 Found=323.1986

EXAMPLE 15B (1α, 3β,5α,7β-1-azatricyclo[3.3.1.1³,7]decan-4α-yl)-3-ethylindolizine-1-carboxamide monohydrochloride##STR33## Procedure

To 3-ethylindolizine-1-carboxylic acid (190 mg, 1.0 mmole) in dry CHCl₃was added oxalyl chloride (184 μl, 2.1 mmole) and the resulting solutionwas stirred for 2 hours. Concentrated in vacuo gave a solid which wasdissolved in CHCl₃ (5 mls)/DMF (0.3 mls) and to the resulting solutionwas then added a solution ofexo-N-(1-azatricyclo[3.3.1.1.]decane-4-amine (140 mgs, 0.92 mmole) andtriethyl amine [280 μl, 2.0 mmole) in CHCl₃ (2 mls). The solution wasthen stirred for 18 hours. The CHCl₃ layer was then washed with 1N NaOH,brine and dried over K₂ CO₃, filtered, and concentrated in vacuo to givea solid. The solid was chromatographed on silica gel eluting with 8% CH₃OH (NH₃ )/CHCl₃ to give 280 mg (70.5%) as the free base. Thehydrochloride salt was made by the same procedure as in Example 15A togive 192 mg (85%) solid.

    ______________________________________                                        Calculated for C.sub.20 H.sub.25 N.sub.3 O.HCl. .35H.sub.2 O                                          Found                                                 ______________________________________                                        C,            65.50         65.96                                             H,             7.35         7.57                                              N,            11.47         11.08                                             Cl,            9.68         9.70                                              ______________________________________                                    

Calculated MS for C₂₀ H₂₅ N₃ O=323.420 Found 323.196

EXAMPLE 16((±)-endo-N-(Hexahydro-1H,2,5β-methano-3aα,6α-cyclopenta[c]pyrrol-4α-yl)-3-ethylimidazo[1,5-a]Pyridine-1-carboxamide,monohydrochloride) ##STR34## Procedure

3-Ethylimidazo[1,5-a]pyridine-1-carboxylic acid (72.9 mg, 0.00038 mol)[preparation described by Bermudez et al. in Journal of MedicinalChemistry, (1990)33, 1928] and 1,1'-carbonyldi-imidazole (62 mg, 0.00038mol) were suspended in DMF (0.5 ml) and the mixture was stirred for 4 h.(±)-Endo-N-(Hexahydro-1H-2,5β-methano-3aα,6aα-cyclopenta[c]Pyrrol-4-amine(53 mg, 0.00038 mol) in DMF (1 ml) was added and the mixture stirred anadditional 40 h. The reaction mixture was concentrated in vacuo to givea residue which was treated with 20% K₂ CO₃ (1 ml) and extracted withCHCl₃ (3X). The combined extracts were washed with water and brine anddried over Na₂ SO₄. Concentration in vacuo gave 127 mg of a solid whichwas chromatographed on silica gel eluting with 2/98 MeOH (NH₃)/CHCl₃ togive the desired amide (43 mg, 36%) as the free base. The free base wasconverted to the hydrochloride salt by dissolving in NCl/MeOH [preparedfrom acetyl chloride (8.8 μl, 0.00014 mol) and MeOH (1 ml)]. Addition ofthis methanolic solution to diethyl ether (75 ml) and filtration gavethe title compound as the hydrochloride salt (39 mg).

MS calcd for C₁₈ H₂₂ N₄ O: 310.1793; found 310.1791.

EXAMPLE 16AN-exo(tetrahydro-1H-pyrrolizin-4(5H)-ylmethyl)-3-ethylimidazo[1,2-a]pyridine-1-carboxamidemonohydrochloride ##STR35## Procedure

3-ethylimidazo[1,5-a]pyridine-1-carboxylic acid (190 mg, 1.0 mmole) wassuspended in CHCl₃ (2 ml). Oxalyl chloride (184 μl, 2.1 mmole) and DMF(1 drop) were added and mixture stirred for 2 hours. Reaction mixturewas concentrated in vacuo, azeotroping once with toluene.

The residue dissolved in CHCl₃ was added a solution ofexo-tetrahydro-1H-pyrrolizin-4(5H)-methylamine (140 mg, 1.0 mmole),triethyl amine (279 μl, 2.0 mmole) in CHCl₃ (2 ml) and the mixturestirred for 18 hours. Organic solution was washed with 1N NaOH, brine,dried over K₂ CO₃, filtered and concentrated to give a crude oil. Oilwas chromatographed on silica gel eluting with 5% CH₃ OH(NH₃ ) CHCl₃ togive 110 mg (35%) of desired compound as the free base. HCl salt wasmade by same method as in Example 15A.

    ______________________________________                                        Calculated for C.sub.18 H.sub.24 N.sub.4 O.HCl.3/4 H.sub.2 O                  ______________________________________                                        C,      57.91     58.15  Calculated MS                                        H,       7.24     6.95   for C.sub.18 H.sub.24 N.sub.4 O                      N,      15.01     14.95            312.42                                     Cl,     12.35     12.25  Found     312.195                                    ______________________________________                                    

EXAMPLE 17(R-N-(1-Azabicyclo[2.2.2]octan-3-yl)imidazo[1,2-a]pyridine-2-carboxamidedihydrochloride) ##STR36## Procedure

The compound of example E (216 mg, 0.001 mol) and1,1'-carbonyldiimidazole (178 mg, 0.001 mol) were suspended in DMF (5ml), and the mixture was stirred for 1 h before addingR-3-aminoquinuolidine dihydrochloride (200 mg, 0,001 mol), synthesizedusing the procedure in European Patent #0280 603. The mixture wasstirred for 18 hours. TIc (30% EtOH/CH₂ Cl₂ /1/10% NH₄ OH) indicatedthat the reaction was complete. Concentration afforded a residue whichwas suspended in water and the pH adjusted to 11 with K₂ CO₃. The solidwhich formed was filtered and purified by radial chromatography [(2 mmplate), gradient elution 25% to 75% i-PrOH/CH₂ Cl₂ /1/10% NH₄ OH] toafford a residue which was converted to the hydrochloride salt bydissolving the residue in i-PrOH and passing HCl gas over the solution.The solid was filtered, washed with i-PrOH and dried in a vacuumdesicator to yield 169 mg (47%) of the title compound.

    ______________________________________                                        Elements  Calc    Found                                                       ______________________________________                                        Carbon    51.61   51.83    C.sub.15 H.sub.18 N.sub.4 O *2.15 HCl *0.1                                    H.sub.2 O*0.15iPrOH                                Hydrogen  6.04    6.06                                                        Nitrogen  15.58   15.44    MW 359.54                                          Chlorine  21.20   21.11                                                       ______________________________________                                    

EXAMPLE 18(S-N-(1-Azabicyclo[2.2.2]octan-3-yl)imidazo[1,2-a]pyridine-2-carboxamidedihydrochloride) ##STR37## Procedure

Employing the compound of example E (216 mg, 0,001 mol),1,1'-carbonyldiimidazole (178 mg, 0.001 mol) DMF (5 ml),S-3-aminoquinuclidine dihydrochloride (200 mg, 0.001 mol) [synthesizedusing the procedure in European Patent #0 280 603], the same proceduredescribed in example 17 was used to afford the title compound (182 mg,50%).

    ______________________________________                                        Elements Calc   Found                                                         ______________________________________                                        Carbon   51.18  51.53   C.sub.15 H.sub.18 N.sub.4 O *2.1 HCl *0.4 H.sub.2                             O*0.2                                                                         i-PrOH                                                Hydrogen 6.19   6.02                                                          Nitrogen 15.30  15.19   MW 366.13                                             Chlorine 20.33  20.09                                                         ______________________________________                                    

EXAMPLE 19 Endo-N-(8-Methyl-8-azabicyclo[3.2.1]octane-3-yl)triazolylpyridine-3-carboxamide)monohydrochloride ##STR38##

Triazolylpyridine-3-carboxylic acid (110 mg, 0.606 mmole)[prepared inaccordance with the procedure in Chem. Ber., 1968, 99, 2918], wassuspended in CH₂ Cl₂ (5 ml). Thionyl chloride (442 μl, 6.60 mmole) andDMF (1 drop) were added and the mixture heated to reflux for 2.5 hr.Solvent was removed via rotary evaporator to give a solid. The solid wasdissolved in CH₂ Cl₂ (5 ml), and a solution ofendo-N-8-methyl-8-azabicyclo[3.2.1]octane-3-amine (85.0 mg, 0.606mmole), triethyl amine (338 μl, 2.43 mmole) in CH₂ Cl₂ (1 ml) was addedand the mixture stirred for 50 hours. Filtration afforded an organicsolution which was chromatographed on silica gel eluting with 10% CH₃OH/1% NH₄ OH/CH₂ Cl₂ to give 145 mg (80%) of the title compound as thefree base. The free base was converted to the hydrochloride salt by themethod described in Example 15A to yield 51 mg (33%) as the HCl salt.

Anal: Calculated for C₁₅ H₁₉ N₃ O·HCl.·2H₂ O C, 55.37 H, 6.01 N, 21.52Cl,10.90 mp=237°-245° C. Found 55.08 6.26 21.97 11.08

EXAMPLE 20 Endo-N-(9-Methyl-9-azabicyclo[3.3.1]nonan-3-yl)triazolylpyr-3-carboxamide)monohydrochloride ##STR39##

Triazolylpyridine-3-carboxlic acid (120.0 mg, 0.661 mmole) was suspendedin CH₂ Cl₂ (0.5 ml). Thionyl chloride (481 μl, 6.61 mmole) and DMF (1drop) were added and the mixture stirred for 2 1/2 hours. Concentrationafforded a solid. The solid was dissolved in CH₂ Cl₂, and a suspensionof endo-N-9-methyl-9-azabicyclo[3.3.1]-nonane-3-amine (150 mg 0.661mmole) and triethyl amine (369 μl, 2.64 mmole) in CH₂ Cl₂ (2 ml) wasadded. The mixture was stirred 18 hours. The contents were washed with5% K₂ CO₃, water, and dried over MgSO₄. Filtration and concentrationgave a foam. The residue was chromatographed on silica 60 eluting with5% CH₃ OH(NH₃ )/CHCl₃ to give 97 mg (49%) of a white foam as the freebase. The free base was converted to the HCl salt by the methoddescribed in Example 15A to give 44 mg of the title compound (71%) as asolid.

Anal: Calculated C₁₆ H₂₁ N₅ O: ·9HCl 1.3H₂ O C, 54.04; H, 6.94; N,19.69; Cl8.97; Found: C, 54.50; H, 6.36; N, 19.05; Cl,9.31

m.p.=225°-233° C.

The compounds herein exhibit 5-HT3 antagonism. 5-HT3 antagonism can bedetermined by the radioligand receptor binding assay as described hereinand in the in vivo Bezold-Jarisch reflex procedure.

Serotonin (5-HT₃)

Procedure

GR65630 binds to the 5-HT₃ receptor. Brain cortices are obtained frommale rats and a membrane fraction prepared by standard techniques. 0.04mg of membrane prep is incubated with 0.2 nM [³ H]-GR656630 for 60minutes at 22° C. Non-specific binding is estimated in the presence of 1uM ICS 205-930. Membranes are filtered and washed 3 times and thefilters are counted to determine [3H]-GR65630 specifically bound.*

Results

Kd=2.46 nM

Bmax=154 fmol/mg protein

% Specific Binding: 70

    ______________________________________                                        Effect of Reference Compounds on                                              [H]-GR65630 Bound (0.2 nM)                                                    Compound IC.sub.50   Ki        Hill Coefficient                               ______________________________________                                        Quipazine                                                                              0.5     nM      0.18 nM   0.86                                       ICS 205-930                                                                            2.2     nM      0.51 nM   1.0                                        5-HT     122     nM      0.39 uM   1.0                                        RU24969  320     nM      1.85 uM   1.0                                        Zacopride                                                                              0.55    nM      0.18 nM   0.86                                       ______________________________________                                    

Kilpatrick G J, Jones B J and Tyers M B. Identification and distributionof 5-HT₃ receptors in rat brain using radioligand binding. Nature, 330:746-748, 1987.

Bezold-Jarisch Reflex

The test sample is administered i.p. (mg/kg) to a group of 3 mice.Thirty minutes later, a 5-HT (0.25 mg/kg i.v.)-induced bradycardia isrecorded in pentobarbital anesthetized animals. A greater than 50percent (>50) reduction in the bradycardic response relative tovehicle-treated control mice is considered significant.

    ______________________________________                                                         Minimum Effective Dose                                       REFERENCE AGENTS:                                                                              (MED), mg/kg                                                 ______________________________________                                        BRL-43694        0.05                                                         cisapride        5                                                            cyproheptadine   5                                                            domperidone      >10                                                          GR-38032         0.5                                                          ketanserin       >10                                                          mecamylamine     2.5                                                          methysergide     >10                                                          metoclopramide   5                                                            scopolamine      2.5                                                          ______________________________________                                    

This method has been described by Saxena, P. R. and Lawang, A., Arch.Int. Pharmacodyn., 277:235-252, 1985.

    ______________________________________                                                TEST PROCEDURE                                                                                 BEZOLD JARISCH                                                 5-HT3 BINDING: REFLEX (Mice);                                                 NG108-15 Cells % Inhibition @                                       Example No.                                                                             IC50           Dose (IP)                                            ______________________________________                                        1         6.3 nM         87%       @ 10                                                 274 nM         73%       @ 3                                                  Ki = 137 nM    68%       @ 1                                                                 N         @ 0.3                                      2                        53%       @ 10                                                                1%        @ 5                                        3         19.34 nM                                                                      99 nM                                                                         Ki = 50 nM                                                          4         500 nM         82%       @ 10                                                 831 nM         2%        @ 3                                                  Ki = 416 nM                                                         5         475 nM         80%       @ 10                                                 628 nM         N         @ 3                                                  Ki = 314 nM                                                         6         2.36 nM                                                                       9.8 nM                                                                        Ki = 4.9 nM                                                         7         17.5 nM                                                                       23 nM                                                                         Ki = 12 nM                                                          8         70 nM          100%      @ 10                                                                95%       @ 5                                                                 88%       @  2.5                                                              82%       @ 0.5                                                               N         @ 0.25                                     9         16 nM                                                                         127 nM                                                                        Ki = 64 nM                                                          10        200 nM         81%       @ 10                                                 243 nM         N         @ 3                                                  Ki = 122 nM                                                         11        >100 nM                                                             12        17 nM          N         @ 10                                       13        23% @ 100 nM   23%       @ 10                                       14                       N         @ 10                                       15        26.33 nM                                                            16        30 nM                                                               ______________________________________                                    

Also embraced within this invention is a class of pharmaceuticalcompositions comprising one or more of the described compounds inassociation with one or more non-toxic, pharmaceutically acceptablecarriers and/or diluents and/or adjuvants (collectively referred toherein as "carrier" materials) and, if desired, other activeingredients. The compounds of the present invention may be administeredby any suitable route, preferably in the form of a pharmaceuticalcomposition adapted to such a route, and in a dose effective for thetreatment intended. Therapeutically effective doses of the compounds ofthe present invention required to prevent or arrest the progress of themedical condition are readily ascertained by one of ordinary skill inthe art. The compounds and composition may, for example, be administeredintravascularly, intraperitoneally, subcutaneously, intramuscularly ortopically.

For oral administration, the pharmaceutical composition may be in theform of, for example, a tablet, capsule, suspension or liquid. Thepharmaceutical composition is preferably made in the form of a dosageunit containing a particular amount of the active ingredient. Examplesof such dosage units are tablets or capsules. These may with advantagecontain an amount of active ingredient from about 1 to 250 mg,preferably from about 25 to 150 mg. A suitable daily dose for a mammalmay vary widely depending on the condition of the patient and otherfactors. However, a dose of from about 0.1 to 3000 mg/kg body weight,particularly from about 1 to 100 mg/kg body weight, may be appropriate.

For therapeutic purposes, the compounds of this invention are ordinarilycombined with one or more adjuvants appropriate to the indicated routeof administration. If administered per os, the compounds may be admixedwith lactose, sucrose, starch powder, cellulose esters of alkanoicacids, cellulose alkyl esters, talc, stearic acid, magnesium stearate,magnesium oxide, sodium and calcium salts of phosphoric and sulfuricacids, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone,and/or polyvinyl alcohol, and then tableted or encapsulated forconvenient administration. Such capsules or tablets may contain acontrolled-release formulation as may be provided in a dispersion ofactive compound in hydroxypropylmethyl cellulose. Formulations forparenteral administration may be in the form of aqueous or non-aqueousisotonic sterile injection solutions or suspensions. These solutions andsuspensions may be prepared from sterile powders or granules having oneor more of the carriers or diluents mentioned for use in theformulations for oral administration. The compounds may be dissolved inwater, polyethylene glycol, propylene glycol, ethanol, corn oil,cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride,and/or various buffers. Other adjuvants and modes of administration arewell and widely known in the pharmaceutical art.

Although this invention has been described with respect to specificembodiments, the details of these embodiments are not to be construed aslimitations. Various equivalents, changes and modifications may be madewithout departing from the spirit and scope of this invention, and it isunderstood that such equivalent embodiments are part of this invention.

What is claimed is:
 1. A compound of the formula ##STR40## thestereoisomers and pharmaceutically acceptable salts thereof, wherein R₁is H or C₁₋₆ alkyl and R₂ is H or halogen;Y represents NH or 0; andwherein k is 1, 1 is 1, j is 0 to 4 and one of R'₃ and R'₄ is H, C₁₋₆alkyl, phenyl or phenyl-C₁₋₃ alkyl, which phenyl moieties may beoptionally substituted by C₁₋₆ alkyl, C₁₋₆ alkoxy, CF₃ or halogen andthe other of R'₃ and R'₄ is H or C₁₋₆ alkyl.
 2. The compound of claim 1which is(endo-N-(1-Azabicyclo[3.3.1]nonan-4-yl)-6-chloroimidazo[1,2a]pyridine-8-carboxamide,dihydrochloride).
 3. The compound of claim 1 which is(endo-N-(1-Azabicyclo[3.3.1]nonan-4-yl)imidazo[1,2-a]pyridine-8carboxamide,dihydrochloride).
 4. A pharmaceutical composition for the treatment ofanxiety, psychoses, depression, substance abuse, cognitive disorders, orgastrointestinal motility disturbances comprising a therapeuticallyeffective amount of a compound of claim 1 and a pharmaceuticallyacceptable carrier or diluent.
 5. A method of treating anxiety,psychoses, depression or gastrointestinal motility disturbancescomprising administering to a subject in need of such treatment atherapeutically effective amount of a compound of claim
 1. 6. A compoundaccording to claim 1 wherein R₁ is H, R₂ is H or halo, Y is NH, j is 0and R'₃ and R'₄ are both H.
 7. A pharmaceutical composition according toclaim 4 wherein R₁ is H and R₂ is H or halo, Y is NH, j is 0 and R'₃ andR'₄ are both H.
 8. The method of claim 5 wherein R₁ is H, R₂ is H orhalo, Y is NH, j is 0 and R'₃ and R'₄ are both H.